Stabilized tretinoin cream emulsion

ABSTRACT

A stabilized cream emulsion of tretinoin, capable of being stored without refrigeration for long periods of time without losing therapeutic effectiveness and while maintaining the uniformity and stability of the cream, contains xanthan gum as the stabilizer.

[451 Sept. 16, 1975 STABILIZED TRETINOIN CREAM EMULSION [75] Inventor:Lanny G. Felty, Jackson, NJ.

[73] Assignee: Johnson & Johnson, New

Brunswick, NJ.

221 Filed: on. 12, 1973 21 Appl. No.2 406,126

[52] US. Cl 424/318; 424/344 [51] Int. Cl. A61K 31/20 [58] Field ofSearch 424/318, 344

[56] References Cited UNITED STATES PATENTS 3,067,038 12/1962 OConnell424/107 3,326,733 6/1967 Colcgrove 149/20 3,355,447 1 l/l967 OConnell260/209 3,623,868 1 1/1971 Cronig 96/48 3,659,025 4/1972 Halleck 424/3613,717,452 2/1973 Gibsen et a1... 424/361 3,729,568 4/1973 Kligman424/318 3,741,805 6/1973 Crotty et a] 134/4 FOREIGN PATENTS ORAPPLICATIONS 906,000 9/1962 United Kingdom 424/344 901,659 7/1962 UnitedKingdom 424/344 Primary ExaminerAlbert T. Meyers AssistantExaminer-Norman A. Drezin [57] ABSTRACT A stabilized cream emulsion oftretinoin, capable of being stored without refrigeration for longperiods of time without losing therapeutic effectiveness and whilemaintaining the uniformity and stability of the cream, contains xanthangum as the stabilizer.

7 Claims, No Drawings STABILIZED TRETINOIN CREAM EMULSION BACKGROUND OFTHE INVENTION 1. Field of the Invention The invention relates to anemulsion cream formulation of tretinoin (all trans-retinoic acid, orVitamin A acid). More particularly, it relates to an emulsion creamformulation of tretinoin which contains xanthan gum as the stabilizer.This product is particularly advantageous for treating suchdermatological disorders as acne vulgaris.

2. Description of the Prior Art Acne vulgaris is a dermatologicaldisorder prevalent in adolescence. It appears most commonly on the faceand trunk of the patient. The basic lesion of acne is the comedo orblackhead" of a pilosebaceous follicle. In its mildest form, only fewcomedos are present, but in its severe form, a multiplicity of severe,persistent comedos are present. Permanent scarring is frequently aconsequence of the severe form of acne.

Acne occurs when there is a filling up of the follicle with a rathertough keratinous material. This impaction of horny material is theWhitehead and blackhead. As a result of bacterial growth in these hornyimpactions, the follicle ruptures, initiating the inflammatory phase ofthe disease which takes the form of pustules, papules, cysts andnodules.

A variety of methods have been used for the treatment of acne, includingthe use of peeling agents, hormone therapy for female patients,antibacterial therapy and general surgical skin planing.

Although the systemic administration of hormones and antibacterials havebeen used with some success, until recently none of the topicaltreatments have been particularly effective.

Vitamin A acid (tretinoin) has been applied topically, (Beer, Von P.,Untersuchungen ueber die Wirkung der Vitamin A-Saeure, Dermatolugica,124: [92-195, March, 1962 and Stiittgen, G., Zur Lokalbehandlung vonKeratosen mit Vitamin A-Saeure, Dermatolugit-u, 124: 6580, February,1962) in those hyperkeratotic disorders which are responsive to hughoral doses of Vitamin A. Among those treated by Beer and Stiittgen werepatients with acne; however, these investigators reported no effectiveresults with Vitamin A acid on acne. British Pat. No. 906,000 discloseda cosmetic preparation containing Vitamin A acid for the regulation ofthe cornification processes of human skin, but no mention is made of theuse of such preparation for acne.

Recently, however, it has been demonstrated that prolonged topicalapplication of Vitamin A acid is effective in the treatment of acne(Kligman, A. M., Topical Vitamin A acid in Acne Vulgaris, Arch Derm.,99: 469-476, April 1969). Kligman utilizes a composition in whichVitamin A acid is dispersed in a watermiscible (substantially oilandfat-free) liquid carrier having high solvating action. The topicalapplication of this Vitamin A acid composition causes irritation of theskin in the treated areas. See US. Pat. No. 3,729,568

issued Apr. 24, 1973, to Albert M. Kligman.

More recently. it has been found that acne can be effectively treatedwith a cream formulation containing tretinoin, or Vitamin A acid. Acream formulation is generally more acceptable to patients than theliquid vehicle from the point of view of aesthetics and ease ofapplication. Moreover, another important advantage of the cream form oftretinoin is that it reduces the side effects normally associated withthe topical application of tretinoin. These side effects, erythema,stinging and itching, may be sufficient to cause the patient todiscontinue the application of tretinoin before it can be fullyeffective upon the acne.

While tretinoin has been marketed in cream form, the prior tretinoincreams of which I am aware were relatively unstable at room temperatureand required refrigeration to ensure chemical stability.

I have discovered an emulsified cream formulation of tretinoin which hasmuch greater stability than prior tretinoin cream formulations,permitting storage for long periods of time without refrigeration, i.e.,at ambient conditions.

SUMMARY OF THE INVENTION More particularly, I have discovered that aparticular stabilizer, xanthan gum, is effective to stabilize emulsioncream formulations of tretinoin. Preferably, in order to emulsify thetretinoin cream formulation, a non-ionic emulsifier is used. Regardlessof the particular emulsifier employed, physical and chemical stabilityis always a problem. Such emulsified systems are known to requirestabilizers to prevent breaking of the emulsion over long periods ofstorage. While many materials, including xanthan gum, have been used asthickeners or stabilizers for cosmetic creams and lotions, I have foundthat xanthan gum has surprisingly superior compatibility with thetretinoin emulsion systems, thus providing a uniquely stable tretinoinemulsion cream formulation.

In general, my invention comprises a cream formulation containing atherapeutically effective amount of tretinoin, a hydrophobic materialselected fromthe liquid and solid fatty acids, fatty alcohols, fattyacid esters, pharmaceutical grades of waxes and hydrocarbons, the latterranging from liquids, thru semisolids such as petrolatum, to solids, andthe like, a non-ionic emulsifier, xanthan gum, a preservative, anantioxidant and water. However, minor amounts of other additives mayoptionally be present. A general formula encompassing tretinoin creamformulations within the scope of my invention is set forth below.(Unless otherwise indicated herein, all amounts are in weight percent.)

General Cream Formula in Yzw/w Tretinoin (all trans-rctinoic acid) 0.0050.5 Xanthan gum 0.1 a 1.0 Non-ionic emulsifier 1.0 l().0 Combination ofliquid and solid fatty acids, fatty alcohols, fatty acid esters and/orother pharmaceutically acceptable hydrophobic materials 15.0 50.0Prcscrvative( s) 0.05 1.0 Antioxidant(s) 0.0] v 1.0 Water q.s. to 100.0Humectant(s) O 10.0 Scquestring agentts) O 0.5 Dye(s) and/or perfumeoil(s) O 0.75 Sunscrecn(s) O 2.5 Topical corticosteroid 0 v 2.0

Based on accelerated aging tests, tretinoin cream emulsions inaccordance with the present invention have been found to have goodchemical and physical stability for at least three years at ambienttemperatures 15- 30 C). In addition, the product is aestheticallyacceptable, having non-greasy properties.

DESCRIPTION OF THE PREFERRED EMBODIMENTS A stabilized cream emulsionformulation of my invention generally comprises from about 0.005 toabout 0.5 weight of tretinoin; from about 0.1 to about 1.0 weightxanthan gum; from about 1% to about by weight of an emulsifier,preferably a non-ionic emulsifier; from about to about 50 weight of acombination of at least one normally liquid and at least one normallysolid hydrophobic material selected from the fatty acids, fatty alcoholsand fatty acid esters wherein the fatty acid moiety has from about 12 toabout carbon atoms, and pharmaceutical grades of waxes and hydrocarbons(liquid and solid); between about 0.05 and 0.75 weight.% of apreservative which prevents bacterial growth in the cream; and fromabout 0.01 to about 1.0 weight of an antioxidant, the balance beingwater. Optionally, minor amounts of such commonly used cosmeticadjuvants, additives and the like as humectants, sequestering agents,dyes, perfume oils and sunscreens may also be included. Moreover, it isalso contemplated that the compositions of my invention may contain, incombination with the tretinoin, such topically active medicaments as theanti-inflammatory corticosteroids. While generally a mixture of a liquidand a solid hydrophobic material is used, this is not essential,particularly where a semisolid such as petrolaturn is employed.

While the tretinoin compositions of my invention have been discussedherein primarily as suitable for use in treating acne, it will beunderstood that these compositions are effective generally for treatingdermatological conditions where tretinoin is indicated. A preferredrange for the concentration of tretinoin in the cream formulation isfrom about 0.02 to about 0.3% by weight, from about 0.05 to about 0.15weight being particularly preferred.

As indicated previously, xanthan gum and related materials have beenused in cosmetic compositions (U.S. Pat. No. 3,659,025) edibleoil-in-water emulsions (U.S. Pat. No. 3,067,038), aqueous gellingcompositions for cleaning and sanitizing (U.S. Pat. No. 3,741,805)gelled explosive compositions (U.S. Pat. No. 3,326,733) agriculturalchemical compositions (U.S. Pat. No. 3,717,452) and gelablephotoprocessing solutions (U.S. Pat. No. 3,623,868). Xanthan gum is ahigh molecular weight polysacharide derived from xantlzamonascampestris, its dominant hexose units being D-glucose, D-mannose andD-glucuronic acid. It is available commercially under the trademarkKeltrol from Kelco Company, Clark, NJ. More detailed descriptions ofthis product can be found in that companys publications, e.g., Keltrol,Technical Bulletin DB No. 18, as well as in Federal Register vol. 34,No. 53 (March 19, 1969). See also the above mentioned patents,particularly U.S. Pat. Nos. 3,623,868 and 3,717,452, as well as U.S.Pat. No. 3,355,447. In the compositions of my invention it must bepresent in a concentration of from about 0.1 to about 1.0 by weight.However, a concentration range for the xanthan gum between about 0.3 andabout 0.5 weight is preferred.

There is no criticality in the particular surfactant employed in thecompositions ofthis invention. In general, however, non-ionicsurfactants are preferred. Of these, the polyoxyalkylene fatty acidesters, more particularly, the polyoxyalkylene stearates are mostcommonly employed. These surfactants are well known in the art. Suitableexamples include: polyoxyethylene oxypropylene stearate, polyoxyl 40stearate, polyethylene glycol 400 monostearate, and polyethylene glycol600 monostearate. It is preferred to employ from about 3 to 1 about 5weight of the surfactant in the compositions of the invention.

The hydrophobic (fatty) materials which can be used in the compositionsof this invention are well known to those skilled in the art. Theyinclude the fatty acids, fatty alcohols and fatty acid esters, whereinthe fatty acid moiety has from about 12 to about 20 carbon atoms, suchas, for example, stearyl alcohol, stearic acid, isopropyl myristate andcetyl alcohol; as well as pharmaceutical grades of beeswax, includingWhite wax, sperm wax, lanolin, mineral oil, etc. As previouslyindicated, cream formulations in accordance with this invention shouldcontain at least one liquid and at least one solid ingredient from thisclass of materials.

Suitable preservatives for the compositions of this invention includebenzyl alcohol, methyl paraben, propyl paraben, sorbic acid, etc. Whileas little as 0.05 weight of these materials may be present, it ispreferred that the composition contain from about 0.2 to about 0.5weight thereof.

The foregoing materials and the cases for their selection are well knownin the art, as is the case with respect to the humectants, sequesteringagents, dyes, antioxidants perfumes and sunscreens which may optionallybe included in the compositions of this invention. Typical examples ofsuch additives are propylene glycol, glycerin, sorbitol, butylatedhydroxytoluene, citric acid, di-alpha tocopherol, ethylenediaminetetraacetic acid and metal salts thereof, sodium hexametaphosphate andamyl paradimethylaminobenzoate.

Examples of antiinflammatory corticosteroids which may be incorporatedin the compositions of the present invention include hydrocortisone,betamethasone benzoate, desfluorotriamcinolone, dexamethasone,dexamethasone acetate, flumethasone pivalate, flumethasone valerate and.deprodone proprionate. When present in the compositions of the presentinvention, their concentration is generally in the range of from about0.1 to about 2.0 weight In use, the compositions of the invention areapplied topically to the area to be treated or protected, at regularintervals, as needed, generally from about 7 to about 21 times per week.The duration of the treatment will depend upon the nature and severityof the condition to be treated as well as the frequency of applicationof the composition. In general, however, improvement is noticeablewithin the first week or two.

The following examples are presented to further illustrate compositionsof the invention without thereby limiting the scope thereof.

Purified water, USP q.$. to 100.0

EXAMPLE 3 EXAMPLE 7-C0ntinued T fillnoin 0.1 lsopropyl Myristzitc 10.0Xunthun gum, food grade 0.3 Polyoxycthylcne 20 stcuryl ether 2.6polyoxyl 4 curing USP 5-O Polyoxvcthylcnc Z stearyl ether 0.3 Stcarylalcohol, USP 3.0 S

i 1 5 perm wax 5 SILJTK, .lcld. lJSP 19.0 cetyl alcohol 7 lsopropylmyristutc, CTFA WU Propylene glycol Butylaled hydroxytoluenc, FCC 0.1clyccryl monoslcurate 10 0 Sorbic acid, NF 0.2 p t Purified water. USPmm mm) qw 0 EXAMPLE 3 l0 As will be obvious to those skilled in the art,many Trctiploin f d 0.03 variations and modifications may be madewithout dc- Xant an gum. 00 grade 5 I Pmynxyl 4U Swarm USP so partingfrom the spirit and scope of the invention. Stcaric acid, USP 12.0 Whatis claimed is: lsopropyl myristatc. CTFA 20.0 t Bmymcd hydroxymlucncvFCC (L 1 1 5 l 1. In a ret noin cream emulsion for topical applica smplua id, NF 03 tion comprising from about 0.005 to about 0.5% by Punficdwumi USP weight of tretinoin, from about 1.0 to about 10.0% by weight ofan emulsifier, from about 15.0 to about EXAMPLE4 50.0% by weight of ahydrophobic material selected Trcn'noin 0,04 from the group consistingof petrolatum, beeswax, 55 E8 100K: sperm wax, lanolin, mineral oil, theliquid and solid siizlill tlcial. u s l 1Z0 fatty acids having fromabout 12 to about 20 carbon LTPIHLPW y z v CTFA 8 atoms, fatty alcoholshaving from about 12 to about 20 -u p a tocop cro .0 Sodiumhcxumcmphusphum (H carbon atoms, and fatty acid esters wherein the fattySorhic acid, NF 0.2 acid moiety has from about 12 to about 20 carbonPunficd USP atoms, from about 0.05 to about 1.0% by weight of apreservative, from about 0.01 to about 1.0% by weight EXAMPLE 5 of anantioxidant, and water, the improvement which Tmimin ()5 comprises alsohaving therein as a stabilizer to prevent Xhmhwl fwd gwdv breaking ofthe emulsion, from about 0.1 to about 1.0% Polyoxyl 40 stearate, USP 5.0b h f h Slcaric acid. USP 12.0 y wclg t O Xant an n m' i' CTFA 2. Theproduct of claim 1 wherein the emulsifier IS a Butylatcdhytlroxytolucnc, FCC 0.1 smbic will NF non-ionic emulsifier. i Perfumeoil 015 3. The product of claim 1 which contains from about pmficd USP m0.3 to about 0.5% by weight of xanthan gum.

4. The roduct of claim 2 wherein the emulsifier is EXAMPl E 6 p selectedfrom the group consisting of polyoxyethylene Tretinoin 0.02 25oxypropylene stearate, polyoxyl 40 stearate, polyximhun gmhrmd grad ethe l c 1400 mon ear-ate l eth l l l Polyethylene gl col 600 monostcurzitc2.75 ylen g y 0 0st p0 y y enc g yco Polyethylene glycol 400monostcaratc 0.7 40 600 monostearate, polyoxyethylene 2O stearyl ethergy 2 and polyoxyethylene 2 stearyl ether. i i tj f lanolin i0 5. Theproduct of claim 1 wherein the preservative is Mineral Oil. NF 7 .2)sorbic acid. Propylene glycol, USP l v Bulylmcd hydroxymlucm FCC 005 6.The product of claim 1 wherein the antioxidant is Citri i USP 0.05 amember selected from the group consisting of butyliii- 3 1 atedhydroxytoluene, and dl-alpha tocopherol.

c a Perfume Oil 015 7. The product of claim 1 wherein the hydrophobicPm'dmumlhmmhcnmm material is selected from the group consisting of astea- Purlficd wzltcr. USP q.s. to 1000 ryl alcohol, petrolatum, stearlcacid, lsopropyl myrls- EXAMPLE 7 tate, cetyl alcohol, beeswax, spermwax, lanolin, min Tmimin (H cral oil and glyceryl monostearate.Flurandrcnolitlc 0.05 Xzinthan gum 0.3 Sorbic acid 0.2 ButylutcdHydroxytolucnc 1

1. IN A TRETINOIN CREAM EMULSION FOR TROPICAL APPLICATION COMPRISINGFROM ABOUT 0.005 TO ABOUT 0.5% BY WEIGHT OF TRETINOIN, FROM ABOUT 1.0 TOABOUT 10.0% BY WEIGHT OF AN EMULSIFIER, FROM ABOUT 15.0 TO ABOUT 50.0%BY WEIGHT OF A HYDROPHOBIC MATERIAL SELECTED FROM THE GROUP CONSISTINGOF PETROLATUM, BEESWAX, SPERM WAX, LANOLIN, MINERAL OIL, THE LIQUID ANDSOLID FATTY ACIDS HAVING FROM ABOUT 12 TO ABOUT 20 CARBON ATOM , FATTYALCOHOLS HAVING FROM ABOUT 12 TO ABOUT 20 CARBON ATOMS, AND FATTY ACIDESTER WHEREIN THE FATTY ACID MOIRTY HAS FROM ABOUT 12 TO ABOUT 20 CARBONATOMS, FROM ABOUT 0.05 TO ABOUT 1.0% BY WEIGHT OF A PRESERVATIVE, FROMABOUT 0.01 TO ABOUT 1.0% BY WEIGHT OF AN ANTIOXIDANT, AND WATER, THEIMPROVEMENT WHICH COMPRISES ALSO HAVING THEREIN AS A STABILIZER TOPREVENT BREAKING OF THE EMULSION, FROM ABOUT 0.1 TO ABOUT 1.0% BY WEIGHTOF XANTHAN GUM.
 2. The product of claim 1 wherein the emulsifier is anon-ionic emulsifier.
 3. The product of claim 1 which contains fromabout 0.3 to about 0.5% by weight of xanthan gum.
 4. The product ofclaim 2 wherein the emulsifier is selected from the group consisting ofpolyoxyethylene 25 oxypropylene stearate, polyoxyl 40 stearate,polyethylene glycol 400 monostearate, polyethylene glycol 600monostearate, polyoxyethylene 20 stearyl ether and polyoxyethylene 2stearyl ether.
 5. The product of claim 1 wherein the preservative issorbic acid.
 6. The product of claim 1 wherein the antioxidant is amember selected from the group consisting of butylated hydroxytoluene,and dl-alpha tocopherol.
 7. The product of claim 1 wherein thehydrophobic material is selected from the group consisting of a stearylalcohol, petrolatum, stearic acid, isopropyl myristate, cetyl alcohol,beeswax, sperm wax, lanolin, mineral oil and glyceryl monostearate.